Hemorrhagic shock results in a disruption to systemic homeostasis and can eventually lead to multiple organ dysfunction syndrome (MODS), which is the cause of 50-80% of deaths in the surgical intensive care units. Because the development of MODS is poorly understood, current treatment is mainly supportive. It is therefore critical to identify key events and factors that lead to the progression of MODS to identify critical points of intervention. The long-range goal of this research is to identify the factors released in response to shock that promote systemic effects that contribute to the development of (MODS). This proposal focuses on the isolation and identification of factor(s) that are present in mesenteric (intestinal) lymph and plasma following traumahemorrhagic shock (T/HS) that suppress bone marrow (BM) cell colony formation, activate neutrophils, and increase red blood cell rigidity. Our central hypothesis is that factors responsible for the BM, PMN and RBC dysfunctions are produced in the gut after T/HS and introduced to the general circulation via the mesenteric lymphatics. This is based on in vitro and in vivo data showing that suppression of BM cell colony formation, PMN activation, and RBC rigidification is observed in rats subjected to T/HS but not T/SS and is abolished by mesenteric lymph-duct ligation. Consequently, the primary goal of this project is to identify the biologically active factors in the lymph and plasma by using a continuum of T/HS lymph/plasma separations where each subseparation is tailored to the characteristics (e.g., protein, lipid, size, charge) of the components present in the sub-fraction that retains toxicity. Identification of these factors will make it possible to study their production, regulation, entry into the lymph and effects on different tissues. This research could help develop new therapeutic modalities to prevent formation of or limit the damage produced by these factors in order to prevent MODS.